The invention relates to slow release formulations.
One of the most important parameters defining the effect of a drug applied to the organism is its physicochemical characteristics. Properties underlying the application of the drug may be acquired during its synthesis or else in the particular dosage form only.
Aside from topically applied drugs, most drugs are delivered through what may be called a xe2x80x9cwater pathxe2x80x9d within the organism. Most organic drugs, on the other hand, are also soluble in hydrophobic media such as lipids. A related characterisitic is the distribution coefficient defined as the ratio of solubility in non-polar (lipids) and polar (water) media. It""s value affects not only the delivery rate of the drug to the target site in the organism, but also the duration of it""s effect.
The best known and simplest method of affecting both the delivery rate and the duration of effect of an active substance in the organism is the creation of it""s salt using a suitable salt-forming ion. So called Hosmeister lyotropic ion series have been established to classify the ions according to the size of their hydration/solvation envelopes which determines the solubility of the salts in a particular environment.
The most important indifferent cation and anion, not contributing to the physiological properties of a drug, are Na+ and CI ions. Interesting salt-forming, though physiologically not fully indifferent anions are carboxylate anions such as those derived from citric, lactic, tartaric, glycolic, gluconic, or glucuronic acids.
Drug salts containing these anions are generally less soluble than chlorides or sulphates and therefore tend to display a prolonged or protracted effect of the drug.
Prolongation of the effect of the active substance of a drug can be attained through the use of a similar salt of the substance having a limited solubility.
Prolongation can also be achieved by fixing the active substance to ionogenic functional groups of a suitable type of polymer.
This invention is directed towards providing a polymer system to achieve slow release of an active drug in the organism.
The invention in particular involves the use of polyanhydroglucuronic acids and salts thereof. The term polyanhydroglucuronic acid and salts there of as used herein also includes copolymers thereof, especially with anhydroglucose. This is hereinafter referred to as PAGA.
Co-pending patent application PCT IE98/00004 describes particular polyanhydroglucuronic acids and salts thereof and a method of preparing such compounds. In particular therefore, the term polyanhydroglucuronic acids and salts thereof includes the acids and salts referred to in this co-pending application.
We have now found that fixation of suitable types of drugs to microdispersed or microfibrillar PAGA, and salts, complex salts, or intermolecular polymer complexes thereof, preferably as prepared according to the method disclosed in PCT IE/98/00004, can be used as a means for preparing drug dosage forms with a significantly protracted effect and a reduced toxicity.
A prolongation of the effect of a drug fixed to this type of polymer chain makes it possible to reduce the amounts dosed and the frequency of dosing and thereby makes the therapy more comfortable for the patient and reduces potential systemic toxicity of the drug, the latter issue being especially of concern with, for instance, certain types of antibiotics or cytostatics.
When the polymer matrix is biodegradable. The matrix, insoluble at the origin, can then be degraded by hydrolysis or an enzyme-assisted hydrolysis in the organism whereby it slowly releases the active substance fixed to the ionogenic groups of the structural units of the biopolymer and makes it free to permeate through biological membranes.
We have found that microdispersed and microfibrillar PAGA, containing uronic carboxyl groups in the polysaccharidic polymer chain, owing to it""s small particle size, high porosity and high specific surface area, and a fully open inner surface, appears to be an ideal biopolymer suitable for physicochemical fixation of a number of biologically active substances.
The open inner surface makes it possible for the molecules of the active substance to uniformly penetrate into the polymer matrix and to get uniformly fixed thereto by way of formation of either a simply salt of an acetate type or a complex salt. This uniformity, in turn, provides for a uniform release of the active substance and for the uniformity of it""s effect in the organism.
Though an appropriate selection of the amount of the active substance, selection of further cations fixed to the polysaccharidic polymer chain, and possibly introduction of a certain density of cross links within the chain, it is possible to influence and vary the rate of the release from the polymer matrix. A pronounced prolongation of the drug effect and reduction of systemic toxicity with, for example, cytostatic drugs can be achieved, and the release of the active substance from the matrix can be well controlled.
Last but not least, a concomittant contribution to the reduction of drug toxicity can be attained owning to the release of glucuronic acid, which is a detoxication agent of a mammalian organism, simultaneously occurring during the biodegradation of the polymer matrix.
According to the invention there is provided a slow release formulation including a biocompatible anionic polysaccharide material containing glucuronic acid in the polymer chain.
Preferably at least 5% of the basic structural units are glucuronic acid.
Preferably the polysaccharide material is polyanhydroglucuronic acid, biocompatible salts thereof, copolymers thereof, or a biocompatible intermolecular complex thereof.
In a preferred embodiment of the invention the biocompatible intermolecular polymer complex is a complex of:
an anionic component comprising a linear or branched polysaccharide chain containing glucuronic acid; and
a non protein cationic component comprising a linear or branched natural, semi-synthetic or synthetic oligomer or polymer.
Preferably at least 5% of the basic structural units of the anionic component are glucuronic acid.
The cationic component preferably contains nitrogen that either carries a positive charge or wherein the positive charge is induced by contact with the polysaccharidic anionic component.
The cationic component may be selected from derivatives of acrylamide, methacrylamide and copolymers thereof. In this case the cationic component is selected from polyacrylamide, copolymer of hydroxyethylmethacrylate and hydroxypropylmetacrylamide, copolymers of acrylamide, butylacrylate, maleinanhydride and/or methylmetacrylate.
In one embodiment the cationic component is a cationised natural polysaccharide.
Preferably the polysaccharide is a starch, cellulose or gum.
The gum is preferably guargumhydroxypropyltriammonium chloride.
Alternatively the cationic component is a synthetic or semi-synthetic polyamino acid. In this case preferably the cationic component is polylysin, polyarginin, or xcex1,xcex2-poly-[N-(2-hydroxyethyl)-DL-aspartamide].
In another embodiment the cationic component is a synthetic anti-fibrinolytic.
In this case preferably the anti-fibrinolytic is a hexadimethrindibromide (polybren).
Alternatively the cationic component is a natural or semi-synthetic peptide.
In this case preferably the peptide is a protamine, gelatine, fibrinopeptide, or derivatives thereof.
In another embodiment the cationic component is an aminoglucane or derivatives thereof.
In this case preferably the aminoglucane is fractionated chitin or its de-acetylated derivative chitosan. The aminoglucane may be of microbial origin or is isolated from the shells of arthropods such as crabs.
In an especially prepared embodiment of the invention the anionic component is polyanhydroglucuronic acid and/or bicompatible salts and/or copolymers thereof.
Most preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain from 8 to 30 percent by weight of carboxyl groups, at least 80 percent by weight of these groups being of the uronic type, at most 5 percent by weight of carbonyl groups, and at most 0.5 percent by weight of bound nitrogen.
Preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain at most 0.2 percent by weight of bound nitrogen.
In a preferred embodiment the molecular mass of the polymeric chain of the anionic component is from 1xc3x97103 to 3xc3x97105 Daltons.
Most preferably the molecular mass of the polymeric chain of the anionic component ranges from 5xc3x97103 to 1.5xc3x97105 Daltons.
In one embodiment of the invention the content of carboxyl groups is in the range of from 12 to 26 percent by weight, at least 95 percent of these groups being of the uronic type.
Preferably the anionic component contains at most 1 percent by weight of carbonyl groups.
In a preferred embodiment the carbonyl groups are intra- and intermolecular 2,6 and 3,6 hemiacetals, 2,4-hemialdals and C2-C3 aldehydes.
In a preferred embodiment the cationic component is gelatine.
In another preferred embodiment the cationic component is chitosan.
The composition may include at least one biocompatible biologically active substance.
Alternatively or additionally the composition includes at least one biologically acceptable adjuvant.
The composition may include at least one pharmaceutically active adjuvant.
In this case the adjuvant may be an anti-ulcer agent such as an antibiotic which is active against Helicobacter pylori e.g. clarithyromycin and/or a H2-antagonist e.g. cimetidine.
The composition may also include bismuth salt.
The composition is preferably in a form for oral administration.
The composition may be in the form of a tablet, pellet, capsule, granule, or microsphere.
We have now found that by preparing polymeric intermolecular complexes (IMC) of glucuronoglucanes, notably microdispersed PAGA, prepared especially according to PCT IE 98/00004 it is possible to enhance the haemostatic effect of the final products on this basis and the properties of the temporary wound cover formed after the haemostasis is achieved such as its flexibility and resistance to cracking on movable parts of the body.
It is also possible to upgrade physicomechanical properties of the final products on this basis. Such IMCs make it possible to prepare application forms whose manufacture from a pure PAGA or their simple salts is extremely difficult. Such application forms includes non-woven textile-like structures or polymeric films. To modify or upgrade the physical mechanical properties it is sufficient to use even a relatively small amount of polymeric counterion while it is possible to obtain suitable application properties within a broad concentration range of the components. The ratio of the glucuronoglucane to polymeric counterion can be 0.99:0.01 to 0.01:0.99.
Another advantage of glucuronoglucane based IMCs is the possibility to control their biological properties such as varying the degree of haemostatis, resorption time, or immunomodulative properties, and the like.
Polymeric cations suitable to form IMCs with glucuronoglucanes prepared for example according to PCT IE 98/00004 may roughly be subdivided to the following groups:
1. Synthetic biocompatible nitrogen-containing oligomers and polymers.
a) Derivatives of acrylamide and methacrylamide and their copolymers [such as polyacrylamide, copolymer of hydroxyethylmetacrylate and hydroxypropylmetacrylamide, copolymer of acrylamide, butylacrylate, maleinanhydride, and methylmetacrylate, and the like], or else cationised natural polysaccharides such as starches, celluloses, or gums such as guargumhydroxypropyltriammonium chloride.
b) Synthetic or semi-synthetic polyaminoacids such as polylysin, polyarginin, xcex1,xcex2-poly-[N-(2-hydroxyethyl)-DL-asparamide. Synthetic antifibrinolytics hexadimethrindibromide (polybren) can also be included in this group.
2. Natural or semi-synthetic peptides such as gelatine, protamines, or fibrinopeptides, and their derivatives.
3. Natural aminoglucanes such as fractionated chitin and its de-acetylated derivative chitosan, of microbial origin or isolated from the shells of arthropods such as crabs.
In preparing IMCs on the basis of PAGA according to the invention these three groups of substances can be combined to obtain required properties of the final product.
In general it can be said that IMCs using substances from 1a and 1b would preferably be used to prepare various types of highly absorbant biocompatible dressing materials in the form of nonwovens, films, plasters, and pads.
IMCs using the substances from 2 and 3 may serve as efficient haemostatic agents for internal applications in the microfibrillar form, in the microdispersed form as dusting powders, in the form of films, granules, tablets or non-woven textile-like structures. Those preparations also display antiadhesive properties.
We have also found out that in the form of film-like cell culture matrices the latter IMCs incorporating PAGA and salts thereof as prepared according to PCT IE 98/00004 have a favourable effect on the growth of fibroblasts and keratinocytes.
While it is also possible to create IMCs using structural scleroproteins of the collagen type as disclosed in WO 9800180A, it is preferable to use the above mentioned groups of substances because of the possibility of contamination of the final product by telopeptides, viruses or pyrogens. Collagen can affect in an uncontrolled manner, the immune response of the organism because formation of antibodies can be provoked by any portion of the collagen structure even though the main determinants occur in the terminal regions of the collagen macromolecule. Removal of telopeptides only partially solves the antigenicity problem (Michaeli et al: Science, 1969, 166, 1522).
By preparing IMCs according to the invention it is possible to essentially enhance properties of the originally prepared glucoronoglucanes such as 1,4 xcex2 PAGA. For instance an intermolecular complex salt of PAGA and gelatine in one single production step can be used to prepare final products in the form of a non woven, film, microdispersed granules, or dispersions. In contrast to collagen, suitably hydrolysed gelatine is well tolerated, has no toxicity or side effects and it is a much less costly raw material. We have found out that this complex has very good haemostatic properties being about 40% higher than the original PAGA calcium sodium salt. This is despite the fact that the gelatine itself only displays a haemostatic effect after an addition of thrombin [Schwartz S. I. et al.: Principles of Surgery, St.Louis: McGraw Hill Co, 1979, p. 122-123]. In this case the absorption in the organism can be controlled by changing the composition of the complex within the range from tens of hours to several months. With an advantage this complex with a higher haemostatic efficiency can be used as an embolisation or microembolisation product. It can also be used to prepare haemostatic layers of highly absorbent multi-layer dressings or resorbable plasters, though more costly polybren or protamines could also be applied.
An important advantage of these IMCs is the fact that the compounds can be prepared within a single manufacturing operation using the hydrolytic process described in PCT IE 98/00004 which makes these products cost effective.
These IMCs can further be modified by biologically active and/or biologically acceptable substances. Because the IMCs prepared by the present procedure are either of a microdispersed or microfibrillar nature, the active substances tend to be bound uniformly and also are uniformly released in the organism without the need for other adjuvants such as micrcrystalline waxes or stearates. However, the addition of such adjuvants is not excluded.
Biologically active substances which can be incorporated into the IMC may involve, for instance, antibiotics carrying at least a weak positive charge in the molecule such as cephalosporins (cephotaxin), aminoglycosides (neomycin, gentamycin, amikacin), penicillins (tikarcilin) or macrolides (erythromycin, clarithromycin) and the like.
In cases where the calcium/sodium salt of PAGA or its IMC complexes according to the invention are used as microembolisation or embolisation agents in regional chemotherapy of malign tumours, suitable types of cytostatics such as adriamycin or derivatives of 1,4-diaminoanthrachinone can be incorporated. It is also possible to use the IMCs as detaching ligands for platinum(II) based cytostatics.
Biologically acceptable substances used for modification of the IMCs include, for instance, glycerol and its polymers (polyglycerols); mono, di, and certain triglycerides; polyethyleneglycols; monopropyleneglycol; block copolymers of polyethyleneoxides and polypropyleneoxides (Pluronic); starches; cyclodextrines; polyvinylalcohols; cellulose and its derivatives; in general, substances that, in the concentrations used, are not irritating or toxic for the living organism while being capable of further optimising the physicomechanical properties of the final product based on the IMCs according to the invention.
The invention will be more clearly understood from the following description thereof given by way of example only.